Recent findings suggest that the cerebral cholinergic system may be involved in the senile decline of cerebral function. Cortical acetylcholine (ACh) synthesis and release decline as a function of age in experimental animals as described by Gibson et al., J. Neurochem., 38, 488 (1982). The primary deficit in patients suffering from Alzheimer's disease is one of cholinergic origin. There is a marked reduction in the number of cholinergic cell bodies in the nucleus basalis of Meynert resulting in a decrease of choline acetyltransferase activity, acetylcholinesterase activity, and acetylcholine synthesis in the cortical and hippocampal projection areas as described by Perry et al., J. Neuro., 40, 503 (1983). Furthermore, the noradrenergic, the dopaminergic, and the serotonergic systems also appear to be deficient in a majority of patients suffering from Alzheimer's disease as described by Davis et al., Psychopharm. Bulletin, 19, 451 (1983). Marked deficit in cognitive performance and cortical presynaptic cholinergic markers can be induced by lesioning of the nucleus basalis magnocellularis which contains the cholinergic cell bodies that send their projections to the cortex as described by Lerer et al., Behav. Neurosci., 99, 661 (1985). These cognitive deficits can be attenuated by cholinergic drugs as described by Haroutunian et al., Life Sci., 37, 945 (1985). Moreover, clinical trials with cholinesterase inhibitors like physostigmine and tetrahydroaminoacridine (THA) have shown limited improvement in cognitive measures in Alzheimer's patients: Davis and Mohs, Am. J. Psychiatry, 139, 1421 (1982) and Summers et al., N. Engl. J. Med., 314, 1241 (1986).
Researchers have attempted to enhance the neuronal function by using drugs which enhance endogenous stimulus-induced neurotransmitter release which would result in an increase of the amount of neurotransmitter solely when its release is triggered by excitation of the cholinergic neuron. Such action should result in an improvement of the signal-to-noise ratio during transmission in the cholinergic function without the ACh overload toxicity that is typical for cholinesterase inhibitors, or without the distortion of temporal patterns in cholinergic transmission, as caused by direct cholinergic agonists.
Compounds which can be used to enhance the neuronal function are discussed in U.S. Pat. No. 4,760,083, issued to Myers et al. on Jul. 26, 1988. U.S. Pat. No. 4,876,259 issued to Myers et al. on Oct. 24, 1989, and in European Patent Application Publication No. 0311010 which was published on Apr. 12, 1989. 3,3-Disubstituted indolines are described which enhance stimulus-induced release of neurotransmitters, specifically acetylcholine, as well as dopamine and serotonin. These compounds were screened for this activity by evaluating their effect on the release of a neurotransmitter, such as acetylcholine (ACh), from rat cerebral cortex slices using a superfusion procedure described by Mulder et al., Brain Res., 70, 372 (1974) as modified according to Nickolson et al., Naunyn Schmied. Arch. Pharmacol., 319, 48 (1982).
This procedure involves dissecting out an area such as the cortex from rat brain. The brain slices were chopped and incubated with a tritium-labeled neurotransmitter or precursor of the neurotransmitter, e.g., tritiated choline. The brain slices take up the precursor to form the neurotransmitter or they take up the neurotransmitter itself. The labeled drain slices are put into superfusion columns and superfused with a Kreb-Ringers solution. A high potassium Ringers solution is introduced which depolarizes the neurons in the brain slices and induces release of the radiolabeled neurotransmitter (S1). After four minutes, the solution is switched back to the regular Kreb-Ringers solution. A test compound is then introduced into the column and the tissues superfused with the test drug containing solution for twelve minutes after which a second high potassium solution is introduced in the presence of the test compound to stimulate release again (S2). The ratio S2/S1 is compared between the test compounds and the control which is run in the absence of any test drugs. Release enhancers would have a larger S2/S1 ratio compared to that of the control. S1 is used as the internal control for each column. One of the disadvantages of this assay is that it cannot be used to screen large numbers of compounds quickly.
Compounds with such activity can be useful in treating cognitive and/or neurological deficiencies and/or mood or mental disturbances such as found in patients suffering from degenerative nervous system disorders, for example, Alzheimer's disease, Parkinson's disease, senile-dementia, multi-infarct dementia, Huntington's disease, mental retardation, myasthenia gravis, etc.